Stahl's Essential Psychopharmacology

4th Edition - 9781107686465

This fully revised edition returns to the essential roots of what it means to become a neurobiologically empowered psychopharmacologist. This remains the essential text for all students and professionals in mental health seeking to understand and utilize current therapeutics.

This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press.

First edition published 1996Second edition published 2000Third edition published 2008Fourth edition published 2013

Printed and bound in the United Kingdom by the MPG Books Group

A catalog record for this publication is available from the British Library

Library of Congress Cataloging in Publication data

ISBN 978-1-107-02598-1 Hardback ISBN 978-1-107-68646-5 Paperback

Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Mood stabilizers

In this chapter, we will define mood stabilizers and will review the various pharmacological
mechanisms of action proposed for mood stabilizers. We will also discuss concepts
about how to use these drugs in clinical practice, including strategies for what to
do if initial treatments fail and how to rationally combine mood stabilizers with
another drug. Our treatment of mood stabilizers in this chapter is at the conceptual
level, not at the pragmatic level. The reader should consult standard drug handbooks
(such as the companion Stahl’s Essential Psychopharmacology: the Prescriber’s Guide) for details of doses, side effects, drug interactions, and other issues relevant
to the prescribing of these drugs in clinical practice.

Definition of a mood stabilizer: a labile label

“There is no such thing as a mood stabilizer” – FDA

“Long live the mood stabilizers” – prescribers

What is a mood stabilizer? Originally, a mood stabilizer was a drug that treated mania
and prevented recurrence of mania, thus “stabilizing” the manic pole of bipolar disorder.
More recently, the concept of mood stabilizer has been defined in a wide-ranging manner,
from “something that acts like lithium,” to “an anticonvulsant used to treat bipolar
disorder,” to “an atypical antipsychotic used to treat bipolar disorder,” with antidepressants
considered as “mood de-stabilizers.” With all this competing terminology, and with
the number of drugs for the treatment of bipolar disorder exploding, the term mood stabilizer has become so confusing that regulatory authorities and some experts now suggest
that it is best to use other terms for agents that treat bipolar disorder.

Rather than the term mood stabilizers, some would argue that there are drugs that can treat any or all of four distinct
phases of the illness (Figures 8-1 and 8-2). Thus, a drug can be “mania-minded” and “treat from above” to reduce symptoms of
mania, and/or “stabilize from above” to prevent relapse and recurrence of mania (Figure 8-1). Furthermore, drugs can be “depression-minded” and “treat from

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Figure 8-1.Mania-minded treatments. Although the ideal “mood stabilizer” would treat both mania and bipolar depression
while also preventing episodes of either pole, in reality there is as yet no evidence
to suggest that any single agent can achieve this consistently. Rather, different
agents may be efficacious for different phases of bipolar disorder. As shown here,
some agents seem to be “mania-minded” and thus able to “treat from above” and/or “stabilize
from above” – in other words, to reduce and/or prevent symptoms of mania.

Save image

Figure 8-2.Depression-minded treatments. Although the ideal “mood stabilizer” would treat both mania and bipolar depression
while also preventing episodes of either pole, as mentioned for Figure 8-1, in reality there is as yet no evidence to suggest that any single agent can achieve
this consistently. Rather, different agents may be efficacious for different phases
of bipolar disorder. As shown here, some agents seem to be “depression-minded” and
thus able to “treat from below” and/or “stabilize from below” – in other words, to
reduce and/or prevent symptoms of bipolar depression.

below” to reduce symptoms of bipolar depression, and/or “stabilize from below” to
prevent relapse and recurrence of depression (Figure 8-2). Not all drugs proven to work in bipolar disorder have all four therapeutic actions.
In this chapter, we will discuss agents that have one or more of these actions in
bipolar disorder, and for historical purposes and simplification, refer to any of
these agents as “mood stabilizers.”

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Preface to the fourth edition

For this fourth edition of Stahl’s Essential Psychopharmacology you will notice there is a new look and feel. With a new layout, displayed over two
columns, and an increased page size we have eliminated redundancies across chapters,
have added significant new material, and yet have decreased the overall size of the
book.

Highlights of what has been added or changed since the 3rd edition include:

Integrating much of the basic neurosciences into the clinical chapters, thus reducing
the number of introductory chapters solely covering basic neurosciences.

Major revision of the psychosis chapter, including much more detailed coverage of
the neurocircuitry of schizophrenia, the role of glutamate, genomics, and neuroimaging.

One of the most extensively revised chapters is on antipsychotics, which now has:

new discussion and illustrations on how the current atypical antipsychotics act upon
serotonin, dopamine, and glutamate circuitry

new discussion of the roles of neurotransmitter receptors in the mechanisms of actions
of some but not all atypical antipsychotics

5HT7 receptors

5HT2C receptors

α1-adrenergic receptors

completely revamped visuals for displaying the relative binding properties of 17 individual
antipsychotics agents, based upon log binding data made qualitative and visual with
novel graphics

reorganization of the known atypical antipsychotics as

the “pines” (peens)

the “dones”

two “pips”

and a “rip”

inclusion of several new antipsychotics

iloperidone (Fanapt)

asenapine (Saphris)

lurasidone (Latuda)

extensive coverage of switching from one antipsychotic to another

new ideas about using high dosing and polypharmacy for treatment resistance and violence

The impulsivity–compulsivity and addiction chapter is another of the most extensively
revised chapters in this fourth edition, significantly expanding the drug abuse chapter
of the third edition to include now a large number of related “impulsive–compulsive”
disorders that hypothetically share the same brain circuitry:

neurocircuitry of impulsivity and reward involving the ventral striatum

neurocircuitry of compulsivity and habits including drug addiction and behavioral
addiction involving the dorsal striatum

update on the neurobiology and available treatments for the drug addictions (stimulants,
nicotine, alcohol, opioids, hallucinogens, and others)

behavioral addictions

major new section on obesity, eating disorders, and food addiction, including the
role of hypothalamic circuits and new treatments for obesity

lorcaserin (Belviq)

phentermine/topiramate ER (Qsymia)

bupropion/naltrexone (Contrave)

zonisamide/naltrexone

obsessive–compulsive and spectrum disorders

gambling, impulsive violence, mania, ADHD and many others

One of the major themes emphasized in this new edition is the notion of symptom endophenotypes, or dimensions of psychopathology that cut across numerous syndromes. This is seen
perhaps most dramatically in the organization of numerous disorders of impulsivity/compulsivity,
where impulsivity and/or compulsivity are present in many psychiatric conditions and
thus “travel” trans-diagnostically without respecting the DSM (Diagnostic and Statistical Manual) of the American Psychiatric Association or the ICD (International Classification of Diseases). This is the future of psychiatry – the matching of symptom endophenotypes to hypothetically
malfunctioning brain circuits, regulated by genes, the environment, and neurotransmitters.
Hypothetically, inefficiency of information processing in these brain circuits creates
symptom expression in various psychiatric disorders that can be changed with psychopharmacologic
agents. Even the DSM recognizes this concept and calls it Research Domain Criteria (or RDoC). Thus, impulsivity and compulsivity can be seen as domains of psychopathology;
other domains include mood, cognition, anxiety, motivation, and many more. Each chapter
in this fourth edition discusses “symptoms and circuits” and how to exploit domains of psychopathology both to become a neurobiologically
empowered psychopharmacologist, and to select and combine treatments for individual
patients in psychopharmacology practice.

What has not changed in this new edition is the didactic style of the first three editions. This text attempts to present the fundamentals of psychopharmacology
in simplified and readily readable form. We emphasize current formulations of disease mechanisms and also drug mechanisms.
As in previous editions, the text is not extensively referenced to original papers,
but rather to textbooks and reviews and a few selected original papers, with only
a limited reading list for each chapter, but preparing the reader to consult more
sophisticated textbooks as well as the professional literature.

The organization of information continues to apply the principles of programmed learning for the reader, namely repetition and interaction, which has been shown to enhance
retention. Therefore, it is suggested that novices first approach this text by going
through it from beginning to end, reviewing only the color graphics and the legends
for those graphics. Virtually everything covered in the text is also covered in the
graphics and icons. Once having gone through all the color graphics in these chapters,
it is recommended that the reader then go back to the beginning of the book, and read
the entire text, reviewing the graphics at the same time. After the text has been
read, the entire book can be rapidly reviewed again merely by referring to the various
color graphics in the book. This mechanism of using the materials will create a certain
amount of programmed learning by incorporating the elements of repetition, as well
as interaction with visual learning through graphics. Hopefully, the visual concepts
learned via graphics will reinforce abstract concepts learned from the written text,
especially for those of you who are primarily “visual learners” (i.e., those who retain
information better from visualizing concepts than from reading about them). For those
of you who are already familiar with psychopharmacology, this book should provide
easy reading from beginning to end. Going back and forth between the text and the
graphics should provide interaction. Following review of the complete text, it should
be simple to review the entire book by going through the graphics once again.

Expansion of Essential Psychopharmacology books

This fourth edition of Essential Psychopharmacology is the flagship, but not the entire fleet, as the Essential Psychopharmacology series has expanded now to an entire suite of products for the interested reader.
For those of you interested in specific prescribing information, there are now three
prescriber’s guides:

For those interested in how the textbook and prescriber’s guides get applied in clinical
practice there is a book covering 40 cases from my own clinical practice:

Case Studies: Stahl’s Essential Psychopharmacology

For teachers and students wanting to assess objectively their state of expertise,
to pursue maintenance of certification credits for board recertification in psychiatry
in the US, and for background on instructional design and how to teach there are two
books:

For those interested in expanded visual coverage of specialty topics in psychopharmacology,
there is the Stahl’s Illustrated series:

Antidepressants

Antipsychotics: Treating Psychosis, Mania and Depression, 2nd edition

Anxiety, Stress, and PTSD

Attention Deficit Hyperactivity Disorder

Chronic Pain and Fibromyalgia

Mood Stabilizers

Substance Use and Impulsive Disorders

Finally, there is an ever-growing edited series of subspecialty topics:

Next Generation Antidepressants

Essential Evidence-Based Psychopharmacology, 2nd edition

Essential CNS Drug Development

Essential Psychopharmacology Online

Now, you also have the option of accessing all these books plus additional features
online by going to Essential Psychopharmacology Online at www.stahlonline.org. We are proud to announce the continuing update of this new website which allows
you to search online within the entire Essential Psychopharmacology suite of products. With publication of the fourth edition, two new features will
become available on the website:

downloadable slides of all the figures in the book

narrated animations of several figures in the textbook, hyperlinked to the online
version of the book, playable with a click

our new journal CNS Spectrums (www.journals.cambridge.org/CNS), of which I am the new editor-in-chief, and which is now the official journal of
the Neuroscience Education Institute (NEI), free online to NEI members. This journal
now features readable and illustrated reviews of current topics in psychiatry, mental
health, neurology, and the neurosciences as well as psychopharmacology

for CME credits for reading the books and the journal, and for completing numerous
additional programs both online and live

for access to the live course and playback encore features from the annual NEI Psychopharmacology
Congress

for access to the NEI Master Psychopharmacology Program, an online fellowship with
certification

plans for expansion to a Cambridge University Health Partners co-accredited online
Masterclass and Certificate in Psychopharmacology, based upon live programs held on
campus in Cambridge and taught by University of Cambridge faculty, including myself,
having joined the faculty there as an Honorary Visiting Senior Fellow

Hopefully the reader can appreciate that this is an incredibly exciting time for the
fields of neuroscience and mental health, creating fascinating opportunities for clinicians
to utilize current therapeutics and to anticipate future medications that are likely
to transform the field of psychopharmacology. Best wishes for your first step on this
fascinating journey.

Stephen M. Stahl, MD, PhD

CME information

Release/expiration dates

Originally released: February 1, 2013

Reviewed and re-released: February 1, 2016

CME credit expires: January 31, 2019

Target audience

This activity has been developed for prescribers specializing in psychiatry. All other health care providers interested in psychopharmacology are welcome for advanced study, especially primary care physicians, nurse practitioners, psychologists, and pharmacists.

Statement of need

Psychiatric illnesses have a neurobiological basis and are primarily treated by pharmacological agents; understanding each of these, as well as the relationship between them, is essential in order to select appropriate treatment for a patient. The field of psychopharmacology has experienced incredible growth; it has also experienced a major paradigm shift from a limited focus on neurotransmitters and receptors to an emphasis as well upon brain circuits, neuroimaging, genetics, and signal transduction cascades.

The following unmet needs and professional practice gaps regarding mental health were revealed following a critical analysis of activity feedback, expert faculty assessment, literature review, and through new medical knowledge:

Mental disorders are highly prevalent and carry substantial burden that can be alleviated through treatment; unfortunately, many patients with mental disorders do not receive treatment or receive suboptimal treatment.

There is a documented gap between evidence-based practice guidelines and actual care in clinical practice for patients with mental illnesses. This gap is due at least in part to lack of clinician confidence and knowledge in terms of appropriate usage of the therapeutic tools available to them.

To help address clinician performance gaps with respect to diagnosis and treatment of mental health disorders, quality improvement efforts need to provide education regarding (1) the fundamentals of neurobiology as it relates to the most recent research regarding the neurobiology of mental illnesses; (2) the mechanisms of action of treatment options for mental illnesses and the relationship to the pathophysiology of the disease states; and (3) new therapeutic tools and research that are likely to affect clinical practice.

Learning objectives

After completing this activity, you should be better able to:

Apply fundamental principles of neurobiology to the assessment of psychiatric disease states

Link the relationship of psychotropic drug mechanism of action to the pathophysiology of disease states

Identify novel research and treatment approaches that are expected to affect clinical practice

Accreditation and credit designation statements

The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The Neuroscience Education Institute designates this enduring material for a maximum of 67.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses:

for all of your CNE requirements for recertification, the ANCC will accept AMA PRA Category 1 Credits™ from organizations accredited by the ACCME. The content of this activity pertains to pharmacology and is worth 67.0 continuing education hours of pharmacotherapeutics.

Physician assistants:

the NCCPA accepts AMA PRA Category 1 Credits™ from organizations accredited by the AMA (providers accredited by the ACCME).

A certificate of participation for completing this activity will also be available.

Optional posttests and CME credit instructions

The estimated time for completion of this activity is 67 hours. Optional certificates of CME credit or participation are available for each topical section of the book (total of twelve sections). There is a fee for each posttest (varies per section) which is waived for NEI members.

Peer review

The content was originally peer-reviewed in 2013 by 3 MDs and a PharmD to ensure the scientific accuracy and medical relevance of information presented and its independence from commercial bias. The content was reviewed again in 2016 to verify it is still up-to-date and accurate. The Neuroscience Education Institute takes responsibility for the content, quality, and scientific integrity of this CME activity.

Disclosures

Disclosed financial relationships with conflicts of interest have been reviewed by the NEI CME Advisory Board Chair and resolved.

Author

Stephen M. Stahl, MD, PhD

Adjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine, La Jolla, CA

Debbi Ann Morrissette, PhD

The 2013 Peer Reviewers and Design Staff had no financial relationships to disclose. The 2016 Peer Reviewer has no financial relationships to disclose.

Disclosure of Off-Label Use

This educational activity may include discussion of unlabeled and/or investigational uses of agents that are not currently labeled for such use by the FDA. Please consult the product prescribing information for full disclosure of labeled uses.

Disclaimer

Participants have an implied responsibility to use the newly acquired information from this activity to enhance patient outcomes and their own professional development. The information presented in this educational activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this educational activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Primary references and full prescribing information should be consulted.